A Next Generation of Biomarkers for Incipient Huntington's Disease Early intervention will be instrumental to slow or even prevent the clinical manifestations of Huntington's disease (HD). To enable early intervention, biomarkers are needed that track disease processes before devastating symptoms develop. Multiple lines of evidence implicate mutant huntingtin-induced transcriptional dysregulation of messenger and microRNAs in the disease pathobiology. Although HD symptoms reflect preferential neuronal death mutant huntingtin is ubiquitously expressed and biochemical changes can be found in peripheral cells and fluids. This creates an opportunity for translation into clinically useful biomarkers. We hypothesize that microRNAs and messenger RNAs can serve as cerebrospinal fluid and blood markers that track the progressive disease process --- before the clinical phenotype manifests. Next- generation sequencing of microRNA transcripts offers advantageous precision, dynamic range, and sensitivity compared to traditional analog gene expression platforms. Here we will use massively parallel sequencing to discover and independently replicate all known and novel microRNA transcripts associated with pre-manifest HD in cerebrospinal fluid and blood of 100 cases and 100 age- and sex-matched controls. Replicated cerebrospinal fluid and blood microRNA markers will then be translated onto a digital, go-to-the-clinic assay platform. Furthermore, messenger RNAs previously linked to manifest HD will be evaluated for use as potential peripheral biomarkers in individuals at pre-manifest disease stages. To build a generally useful launch platform for biological markers of incipient HD we will establish a cerebrospinal fluid and blood RNA bio-bank linked to PREDICT-HD -- a national resource for the development of molecular markers designed to guide treatment of onset disease. This study will discover and replicate bio-fluid transcripts potentialy useful for monitoring disease processes prior to the onset of clinical symptoms. If confirmed, this next generation of biomarkers will transform clinical trial design and will enable earlier and more effective intervention.